Torimoto et al. Cardiovascular Diabetology (2015) 14:25 DOI 10.1186/s12933-015-0188-1

CARDIO VASCULAR DIABETOLOGY

ORIGINAL INVESTIGATION

Open Access

Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus Keiichi Torimoto, Yosuke Okada, Hiroko Mori, Takashi Otsuka, Mayuko Kawaguchi, Megumi Matsuda, Fumi Kuno, Kei Sugai, Satomi Sonoda, Maiko Hajime, Kenichi Tanaka, Tadashi Arao and Yoshiya Tanaka*

Abstract Background: Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to their indirect effects on postprandial glucose and lipid metabolism. GLP-1 analogs are also reported to inhibit postprandial vascular endothelial dysfunction. This study examined whether the GLP-1 analog exenatide inhibits postprandial vascular endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). Methods: Seventeen patients with T2DM underwent a meal tolerance test to examine changes in postprandial vascular endothelial function and in glucose and lipid metabolism, both without exenatide (baseline) and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was determined using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide tests. Results: The natural logarithmically-scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. The use of exenatide resulted in a significant decrease in triglycerides (TG) area under the curve and coefficient of variation (CV). The change in L_RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L_RHI, contributing to 41% of the observed change. Conclusions: Exenatide inhibited postprandial vascular endothelial dysfunction after the meal loading test, suggesting that exenatide has a multiphasic anti-atherogenic action involving not only glucose but also lipid metabolism. Trial registration: ClinicalTrials.gov: UMIN000015699. Keywords: Exenatide, Reactive hyperemia index (RHI), T2DM, Endothelium function

Background Patients with type 2 diabetes mellitus (T2DM) are at high risk for development of life-threatening atherosclerotic disease compared with healthy persons. For example, the risk of coronary artery disease is 2.0 times higher, and the risk of cerebral infarction is 2.3 times higher in these patients [1]. It is presumed that vascular endothelial dysfunction precedes clinically-evident diabetic macrovasculopathy [2] and that the former is due to various factors such as abnormal glucose and lipid * Correspondence: [email protected] First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

metabolism, inflammation, hypertension, obesity, sedentary life style, smoking, high salt intake, and menopause [3]. Among these factors, it seems that postprandial changes in glucose and lipid metabolism are particularly important risk factors for vascular endothelial dysfunction [4]. Both clinical and experimental evidences suggest that oxidative stress and hypercytokinemia are associated with postprandial hyperglycemia [5] and that postprandial hyperlipidemia enhances the progression of atherosclerosis in patients with T2DM [6]. Therefore, correction of postprandial metabolic disorders and inhibition of vasculopathy through the above pathways could potentially prevent the progression of atherosclerosis.

© 2015 Torimoto et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Torimoto et al. Cardiovascular Diabetology (2015) 14:25

Previous studies reported that incretin analogs do not only indirectly correct postprandial glucose and lipid metabolism [7], but they also inhibit vascular endothelial dysfunction by their direct protective effects on the vascular endothelium, such as enhancement of nitric oxide (NO) production [8] and anti-inflammatory action [9]. In actual clinical settings, long-term administration of sitagliptin is reported to improve vascular endothelial function [10] and exert anti-arteriosclerosis action [11]. Clinically, glucagon-like peptide-1 (GLP-1) receptor agonists are known to improve pro-atherosclerosis factors, such as glucose metabolism, lipid metabolism, blood pressure, and body weight and that their long-term effects include improvement of vascular endothelial function. In addition, one study reported that continuous intravenous infusion of GLP-1 resulted in short-term, blood glucose-independent improvement of vascular endothelial dysfunction [12]. To our knowledge, only a few studies have verified the effects of GLP-1 receptor agonists on postprandial vascular endothelial dysfunction in daily clinical practice, and only little is known at present on the mechanism of the inhibitory effects of these drugs on vascular endothelial dysfunction. The present study examined the effects of exenatide, a GLP-1 receptor agonist, on postprandial vascular endothelial dysfunction after meal loading test in Japanese patients with T2DM.

Methods

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Study design

All 17 patients with T2DM were admitted to the hospital and underwent meal tolerance test to examine changes in postprandial endothelial function and changes in glucose and lipid metabolism (day 1). The test was repeated the next day 15 min after subcutaneous injection of 10 μg exenatide (Byetta®; AstraZeneca K.K., Osaka, Japan) (day 2). Both tests were carried out early in the morning after 12 h of fasting. With regard to the meal tolerance test, a test meal (total 450 kcal; 51.4% carbohydrate, 33.3% fat, and 15.3% protein, a recipe proposed by a working group of the Japan Diabetes Society) [13] was used, and blood was analyzed before and 30, 60, 120, and 240 min after meal loading to evaluate changes in glucose and lipid metabolism. In addition, vascular endothelial function was evaluated before and 120 min after meal loading, using a peripheral arterial tonometry (PAT) device (EndoPAT2000; Itamar Medical, Caesarea, Israel). The evaluation items related to glucose metabolism included plasma glucose and plasma immunoreactive insulin (IRI). The evaluation items related to lipid metabolism were triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The area under the curve (AUC) and the coefficient of variation (CV) were calculated for plasma glucose and IRI based on data obtained at 5 measurement points from 0 to 240 min. The primary endpoint was changes in vascular endothelial function at 0 and 120 min after meal loading test conducted after exenatide, relative to the control (test without exenatide).

Study subjects

This study included 17 patients with T2DM who were admitted to the University of Occupational and Environmental Health Hospital (UOEH) or Wakamatsu Hospital of UOEH between June 2011 and February 2014 and who met the following inclusion criteria: 1) age 20 to less than 80 years; 2) no change in treatment with oral glucose-lowering agents, lipid-lowering agents, and anti-hypertensive agents during the 12 weeks preceding enrollment; and 3) ongoing treatment by diet regimen alone or by therapy with sulfonylurea, sulfonylurea plus biguanide, or sulfonylurea plus thiazolidine derivatives. Patients who met any of the following criteria were excluded from the study: 1) treatment of diabetes with insulin; 2) experience of episodes of diabetic ketoacidosis, nonketotic hyperosmolar coma, infection, or acute coronary syndrome; 3) pregnancy or possible pregnancy; 4) history of stroke or ischemic heart disease within the preceding 6 months; 5) history of pancreatitis; and 6) cardiac arrhythmia. This study was approved by the ethics committee of the UOEH, and the subjects received written information about the study and gave consent to participate in the study.

Noninvasive vascular function test

The PAT-based method used for digital assessment of vascular function has been described in detail previously [14]. After an acclimatization period 30 min in a room controlled for temperature and light in the fasting state, the baseline pulse amplitude was recorded during a period of 5 min before the induction of ischemia. The latter was induced by placing the sphygmomanometer cuff on the upper arm, while the opposite arm served as a control. The PAT probes were placed on one finger of each hand. After 5 min, the blood pressure cuff was inflated to 60 mmHg above the systolic pressure or 200 mmHg for 5 min and then deflated to induce reactive hyperemia. As a measure of reactive hyperemia, the reactive hyperemia index (RHI) was calculated as the ratio of the average amplitude of the PAT signal over 1 min beginning 1.5 min after cuff deflation (control arm, A; occluded arm, C) divided by the average amplitude of the PAT signal over the 2.5-min time period before cuff inflation (baseline) (control arm, B; occluded arm, D). Thus, RHI = (C/D)/(A/B) × baseline correction. Because RHI has a heteroscedastic error structure, we used natural logarithm transformation in all analyses.

Torimoto et al. Cardiovascular Diabetology (2015) 14:25

Measurement of blood HbA1c, plasma glucose, IRI and serum lipids

Blood samples were collected early in the morning after at least 12-h fasting, through a venous line placed in the median vein using an indwelling catheter. Plasma lipid was measured with a Hitachi 7350 autoanalyzer (Hitachi Co., Tokyo, Japan). HDL-C, and triglycerides levels were determined by using an enzymatic method, and both enzymatic method and direct technique were used for LDL-C. The insulin resistance index (homeostasis model assessment of insulin resistance) was calculated according to the formula: fasting IRI (mU/L) × fasting glucose (mg/dL)/405. Hemoglobin Alc (HbA1c) was measured by high-pressure liquid chromatography using the Tosoh HLC-723 G8 (Tosoh Co., Kyoto, Japan). The HbAlc level was obtained as a national glycohemoglobin standardization program value by adding 0.4% to the value expressed as the conventional Japanese standard substance value [15].

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Table 1 Baseline characteristics Age (years)

53.2 ± 2.6

Gender (male/female)

13/2

Body mass index (kg/m2)

27.1 ± 1.5

Duration of diabetes (years)

7.0 ± 1.0

Diabetes complication Neuropathy

9 (60.0)

Retinopathy

2 (13.3)

Nephropathy

0 (0.0)

Diabetes therapy Diet only

2 (13.3)

Sulfonylurea

12 (80.0)

Pioglitazone

0 (0.0)

Metformin

3 (20.0)

Other treatments Lipid-lowering drugs

4 (26.7)

Antihypertensive drugs

5 (48.8)

Statistical analysis

Current smokers

9 (60.0)

Values are expressed as mean ± standard error. Hypoglycemia, requiring glucose intake, developed in two patients during the meal tolerance test after exenatide administration. Excluding these two patients, the analysis included 15 patients. Wilcoxon’s signed rank test was used to compare natural logarithmic-scaled RHI (L_RHI) values at 0 or 120 min after the baseline and exenatide meal loading tests. The Friedman test was used to compare various parameters at 0, 30, 60, 120, and 240 min after meal loading. Spearman’s correlation method was used for analysis of the correlation between L_RHI and changes in glucose metabolism or lipid metabolism. Multivariate analysis used the difference between changes in L_RHI in the baseline and exenatide meal tolerance tests as the dependent variable. The independent variables were age, sex, body mass index (BMI), disease duration, and differences between changes in blood glucose AUC, changes in triglycerides CV, and changes in HDL-C CV without exenatide compared with exenatide administration. The step-up procedure was used for this analysis. Statistical analyses were conducted using SPSS Statistical Software version 19.0 (SPSS Inc., Chicago, IL), and the results were regarded as significant when the p value was

Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus.

Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to thei...
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